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Loss of Transient Receptor Potential Ankyrin 1 Channel Deregulates Emotion, Learning and Memory, Cognition, and Social Behavior in Mice

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Abstract

The transient receptor potential ankyrin 1 (TRPA1) channel is a non-selective cation channel that helps regulate inflammatory pain sensation and nociception and the development of inflammatory diseases. However, the potential role of the TRPA1 channel and the underlying mechanism in brain functions are not fully resolved. In this study, we demonstrated that genetic deletion of the TRPA1 channel in mice or pharmacological inhibition of its activity increased neurite outgrowth. In vivo study in mice provided evidence of the TRPA1 channel as a negative regulator in hippocampal functions; functional ablation of the TRPA1 channel in mice enhanced hippocampal functions, as evidenced by less anxiety-like behavior, and enhanced fear-related or spatial learning and memory, and novel location recognition as well as social interactions. However, the TRPA1 channel appears to be a prerequisite for motor function; functional loss of the TRPA1 channel in mice led to axonal bundle fragmentation, downregulation of myelin basic protein, and decreased mature oligodendrocyte population in the brain, for impaired motor function. The TRPA1 channel may play a crucial role in neuronal development and oligodendrocyte maturation and be a potential regulator in emotion, cognition, learning and memory, and social behavior.

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References

  1. Fernandes ES, Fernandes MA, Keeble JE (2012) The functions of TRPA1 and TRPV1: moving away from sensory nerves. Br J Pharmacol 166(2):510–521

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Koivisto A, Hukkanen M, Saarnilehto M, Chapman H, Kuokkanen K, Wei H, Viisanen H, Akerman KE et al (2012) Inhibiting TRPA1 ion channel reduces loss of cutaneous nerve fiber function in diabetic animals: sustained activation of the TRPA1 channel contributes to the pathogenesis of peripheral diabetic neuropathy. Pharmacol Res 65(1):149–158

    Article  CAS  PubMed  Google Scholar 

  3. García-Añoveros J, Nagata K (2007) TRPA1. Handb Exp Pharmacol 179:347–362

    Article  Google Scholar 

  4. Birrell MA, Belvisi MG, Grace M, Sadofsky L, Faruqi S, Hele DJ, Maher SA, Freund-Michel V et al (2009) TRPA1 agonists evoke coughing in guinea pig and human volunteers. Am J Respir Crit Care Med 180(11):1042–1047

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Caterina MJ (2007) Chemical biology: sticky spices. Nature 445(7127):491–492

    Article  CAS  PubMed  Google Scholar 

  6. Doihara H, Nozawa K, Kawabata-Shoda E, Kojima R, Yokoyama T, Ito H (2009) Molecular cloning and characterization of dog TRPA1 and AITC stimulate the gastrointestinal motility through TRPA1 in conscious dogs. Eur J Pharmacol 617(1–3):124–129

    Article  CAS  PubMed  Google Scholar 

  7. Earley S, Gonzales AL, Crnich R (2009) Endothelium-dependent cerebral artery dilation mediated by TRPA1 and Ca2 + −Activated K+ channels. Circ Res 104(8):987–994

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. El Andaloussi-Lilja J, Lundqvist J, Forsby A (2009) TRPV1 expression and activity during retinoic acid-induced neuronal differentiation. Neurochem Int 55(8):768–774

    Article  PubMed  Google Scholar 

  9. Louhivuori LM, Bart G, Larsson KP, Louhivuori V, Näsman J, Nordström T, Koivisto AP, Akerman KE (2009) Differentiation dependent expression of TRPA1 and TRPM8 channels in IMR-32 human neuroblastoma cells. J Cell Physiol 221(1):67–74

    Article  CAS  PubMed  Google Scholar 

  10. Ernsberger U (2009) Role of neurotrophin signalling in the differentiation of neurons from dorsal root ganglia and sympathetic ganglia. Cell Tissue Res 336(3):349–384

    Article  CAS  PubMed  Google Scholar 

  11. Wu D, Huang W, Richardson PM, Priestley JV, Liu M (2008) TRPC4 in rat dorsal root ganglion neurons is increased after nerve injury and is necessary for neurite outgrowth. J Biol Chem 283(1):416–426

    Article  CAS  PubMed  Google Scholar 

  12. Hjerling-Leffler J, Alqatari M, Ernfors P, Koltzenburg M (2007) Emergence of functional sensory subtypes as defined by transient receptor potential channel expression. J Neurosci 27(10):2435–2443

    Article  CAS  PubMed  Google Scholar 

  13. Jo KD, Lee KS, Lee WT, Hur MS, Kim HJ (2013) Expression of transient receptor potential channels in the ependymal cells of the developing rat brain. Anat Cell Biol 46(1):68–78

    Article  PubMed  PubMed Central  Google Scholar 

  14. Shigetomi E, Jackson-Weaver O, Huckstepp RT, O’Dell TJ, Khakh BS (2013) TRPA1 channels are regulators of astrocyte basal calcium levels and long-term potentiation via constitutive D-serine release. J Neurosci 33(24):10143–10153

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Clarke LE, Attwell D (2011) An astrocyte TRP switch for inhibition. Nat Neurosci 15(1):3–4

    Article  PubMed  Google Scholar 

  16. Shigetomi E, Tong X, Kwan KY, Corey DP, Khakh BS (2011) TRPA1 channels regulate astrocyte resting calcium and inhibitory synapse efficacy through GAT-3. Nat Neurosci 15(1):70–80

    Article  PubMed  PubMed Central  Google Scholar 

  17. Coque L, Mukherjee S, Cao JL, Spencer S, Marvin M, Falcon E, Sidor MM, Birnbaum SG et al (2011) Specific role of VTA dopamine neuronal firing rates and morphology in the reversal of anxiety-related, but not depression-related behavior in the ClockΔ19 mouse model of mania. Neuropsychopharmacology 36(7):1478–1488

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lee PC, Dodart JC, Aron L, Finley LW, Bronson RT, Haigis MC, Yankner BA, Harper JW (2013) Altered social behavior and neuronal development in mice lacking the Uba6-Use1 ubiquitin transfer system. Mol Cell 50(2):172–184

    Article  PubMed  PubMed Central  Google Scholar 

  19. Beutler LR, Eldred KC, Quintana A, Keene CD, Rose SE, Postupna N, Montine TJ, Palmiter RD (2011) Severely impaired learning and altered neuronal morphology in mice lacking NMDA receptors in medium spiny neurons. PLoS One 6(11), e28168

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Paus T, Zijdenbos A, Worsley K, Collins DL, Blumenthal J, Giedd JN, Rapoport JL, Evans AC (1999) Structural maturation of neural pathways in children and adolescents: in vivo study. Science 283(5409):1908–1911

    Article  CAS  PubMed  Google Scholar 

  21. Kuhn PL, Petroulakis E, Zazanis GA, McKinnon RD (1995) Motor function analysis of myelin mutant mice using a rotarod. Int J Dev Neurosci 13(7):715–722

    Article  CAS  PubMed  Google Scholar 

  22. Sampaio-Baptista C, Khrapitchev AA, Foxley S, Schlagheck T, Scholz J, Jbabdi S, DeLuca GC, Miller KL et al (2013) Motor skill learning induces changes in white matter microstructure and myelination. J Neurosci 33(50):19499–19503

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Schmithorst VJ, Wilke M, Dardzinski BJ, Holland SK (2005) Cognitive functions correlate with white matter architecture in a normal pediatric population: a diffusion tensor MRI study. Hum Brain Mapp 26(2):139–147

    Article  PubMed  PubMed Central  Google Scholar 

  24. Yurgelun-Todd DA, Killgore WD, Young AD (2002) Sex differences in cerebral tissue volume and cognitive performance during adolescence. Psychol Rep 91(3 Pt 1):743–757

    Article  PubMed  Google Scholar 

  25. Casey BJ, Giedd JN, Thomas KM (2000) Structural and functional brain development and its relation to cognitive development. Biol Psychol 54(1–3):241–257

    Article  CAS  PubMed  Google Scholar 

  26. Rosenberg SS, Spitzer NC (2011) Calcium signaling in neuronal development. Cold Spring Harb Perspect Biol 3(10):a004259

    Article  PubMed  PubMed Central  Google Scholar 

  27. Chattopadhyay N, Espinosa-Jeffrey A, Tfelt-Hansen J, Yano S, Bandyopadhyay S, Brown EM, de Vellis J (2008) Calcium receptor expression and function in oligodendrocyte commitment and lineage progression: potential impact on reduced myelin basic protein in CaR-null mice. J Neurosci Res 86(10):2159–2167

    Article  CAS  PubMed  Google Scholar 

  28. Pfeiffer SE, Warrington AE, Bansal R (1993) The oligodendrocyte and its many cellular processes. Trends Cell Biol 3(6):191–197

    Article  CAS  PubMed  Google Scholar 

  29. Takeda M, Nelson DJ, Soliven B (1995) Calcium signaling in cultured rat oligodendrocytes. Glia 14(3):225–236

    Article  CAS  PubMed  Google Scholar 

  30. Mato S, Victoria Sánchez-Gómez M, Matute C (2010) Cannabidiol induces intracellular calcium elevation and cytotoxicity in oligodendrocytes. Glia 58(14):1739–1747

    Article  PubMed  Google Scholar 

  31. Chattopadhyay N, Ye CP, Yamaguchi T, Kifor O, Vassilev PM, Nishimura R, Brown EM (1998) Extracellular calcium-sensing receptor in rat oligodendrocytes: expression and potential role in regulation of cellular proliferation and an outward K+ channel. Glia 24(4):449–458

    Article  CAS  PubMed  Google Scholar 

  32. Jamain S, Radyushkin K, Hammerschmidt K, Granon S, Boretius S, Varoqueaux F, Ramanantsoa N, Gallego J et al (2008) Reduced social interaction and ultrasonic communication in a mouse model of monogenic heritable autism. Proc Natl Acad Sci U S A 105(5):1710–1715

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Leach JB, Brown XQ, Jacot JG, Dimilla PA, Wong JY (2007) Neurite outgrowth and branching of PC12 cells on very soft substrates sharply decreases below a threshold of substrate rigidity. J Neural Eng 4(2):26–34

    Article  PubMed  Google Scholar 

  34. Wang X, Wang Z, Yao Y, Li J, Zhang X, Li C, Cheng Y, Ding G, Liu L, Ding Z (1813) Essential role of ERK activation in neurite outgrowth induced by α-lipoic acid. Biochim Biophys Acta 5:827–838

    Google Scholar 

  35. Caceres A, Mautino J, Kosik KS (1992) Suppression of MAP2 in cultured cerebellar macroneurons inhibits minor neurite formation. Neuron 9(4):607–618

    Article  CAS  PubMed  Google Scholar 

  36. Wu PY, Lin YC, Chang CL, Lu HT, Chin CH, Hsu TT, Chu D, Sun SH (2009) Functional decreases in P2X7 receptors are associated with retinoic acid-induced neuronal differentiation of Neuro-2a neuroblastoma cells. Cell Signal 21(6):881–891

    Article  CAS  PubMed  Google Scholar 

  37. Story GM, Peier AM, Reeve AJ, Eid SR, Mosbacher J, Hricik TR, Earley TJ, Hergarden AC (2003) ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated b cold temperatures. Cell 112(6):819–829

    Article  CAS  PubMed  Google Scholar 

  38. Latorre R, Brauchi S, Orta G, Zaelzer C, Vargas G (2007) ThermoTRP channels as modular proteins with allosteric gating. Cell Calcium 42(4–5):427–438

    Article  CAS  PubMed  Google Scholar 

  39. Obata K, Katsura H, Mizushima T, Yamanaka H, Kobayashi K, Dai Y, Fukuoka T, Tokunaga A (2005) TRPA1 induced in sensory neuron contributes to cold hyperalgesia after inflammation and nerve injury. J Clin Invest 115(9):2393–2401

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. del Camino D, Murphy S, Heiry M, Barrett LB, Earley TJ, Cook CA, Petrus MJ, Zhao M (2010) TRPA1 contributes to cold hypersensitivity. J Neurosci 30(45):15165–15174

    Article  PubMed  PubMed Central  Google Scholar 

  41. Chen J, Joshi SK, Di Domenico S, Perner RJ, Mikusa JP, Gauvin DM, Segreti JA, Han P (2011) Selective blockade of TRPA1 channel attenuates pathological pain without altering noxious cold sensation or body temperature regulation. Pain 152(5):1165–1172

    Article  CAS  PubMed  Google Scholar 

  42. de Moura JC, Noroes MM, Rachetti Vde P, Soares BL, Preti D, Nassini R, Materazzi S, Marone IM, Minocci D, Geppetti P, Gavioli EC, André E (2014) The blockade of transient receptor potential ankirin 1 (TRPA1) signalling mediates antidepressant- and anxiolytic-like actions in mice. Br J Pharmacol 171(18):4289–4299

    Article  PubMed  PubMed Central  Google Scholar 

  43. Steinman L (2009) A molecular trio in relapse and remission in multiple sclerosis. Nat Rev Immunol 9(6):440–447

    Article  CAS  PubMed  Google Scholar 

  44. Wang GX, Poo MM (2005) Requirement of TRPC channels in netrin-1-induced chemotropic turning of nerve growth cones. Nature 434(7035):898–904

    Article  CAS  PubMed  Google Scholar 

  45. Hamilton NB, Kolodziejczyk K, Kougioumtzidou E, Attwell D (2016) Proton-gated Ca(2+)-permeable TRP channels damage myelin in conditions mimicking ischaemia. Nature 529(7587):523–527

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Sofroniew MV, Vinters HV (2010) Astrocytes: biology and pathology. Acta Neuropathol 119(1):7–35

    Article  PubMed  Google Scholar 

  47. Sidoryk-Wegrzynowicz M, Wegrzynowicz M, Lee E, Bowman AB, Aschner M (2011) Role of astrocytes in brain function and disease. Toxicol Pathol 39(1):115–123

    Article  PubMed  Google Scholar 

  48. Borges K, McDermott D, Irier H, Smith Y, Dingledine R (2006) Degeneration and proliferation of astrocytes in the mouse dentate gyrus after pilocarpine-induced status epilepticus. Exp Neurol 201(2):416–427

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Bambrick LL, Yarowsky PJ, Krueger BK (2003) Altered astrocyte calcium homeostasis and proliferation in theTs65Dn mouse, a model of Down syndrome. J Neurosci Res 73(1):89–94

    Article  CAS  PubMed  Google Scholar 

  50. Cornell-Bell AH, Finkbeiner SM, Cooper MS, Smith SJ (1990) Glutamate induces calcium waves in cultured astrocytes: long-range glial signaling. Science 247(4941):470–473

    Article  CAS  PubMed  Google Scholar 

  51. Morita M, Higuchi C, Moto T, Kozuka N, Susuki J, Itofusa R, Yamashita J, Kudo Y (2003) Dual regulation of calcium oscillation in astrocytes by growth factors and pro-inflammatory cytokines via the mitogen-activated protein kinase cascade. J Neurosci 23(34):10944–10952

    CAS  PubMed  Google Scholar 

  52. Desai BN, Clapham DE (2005) TRP channels and mice deficient in TRP channels. Pflugers Arch 451(1):11–18

    Article  CAS  PubMed  Google Scholar 

  53. Riccio A, Li Y, Tsvetkov E, Gapon S, Yao GL, Smith KS, Engin E, Rudolph U, Bolshakov VY, Clapham DE (2014) Decreased anxiety-like behavior and Gαq/11-dependent responses in the amygdala of mice lacking TRPC4 channels. J Neurosci 34(10):3653–3667

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Marsch R, Foeller E, Rammes G, Bunck M, Kössl M, Holsboer F, Zieglgänsberger W, Landgraf R, Lutz B, Wotjak CT (2007) Reduced anxiety, conditioned fear, and hippocampal long-term potentiation in transient receptor potential vanilloid type 1 receptor-deficient mice. J Neurosci 27(4):832–839

    Article  CAS  PubMed  Google Scholar 

  55. Ahmmed GU, Malik AB (2005) Functional role of TRPC channels in the regulation of endothelial permeability. Pflugers Arch 451(1):131–142

    Article  CAS  PubMed  Google Scholar 

  56. Hellwig N, Albrecht N, Harteneck C, Schultz G, Schaefer M (2005) Homo- and heteromeric assembly of TRPV channel subunits. J Cell Sci 118(Pt 5):917–928

    Article  CAS  PubMed  Google Scholar 

  57. Su KH, Lin SJ, Wei J, Lee KI, Zhao JF, Shyue SK, Lee TS (2014) The essential role of transient receptor potential vanilloid 1 in simvastatin-induced activation of endothelial nitric oxide synthase and angiogenesis. Acta Physiol (Oxf) 212(3):191–204

    Article  CAS  Google Scholar 

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Acknowledgments

The authors thank Laura Smales for her help in language editing. This study was supported by grants from Ministry of Science and Technology (102-2628-B-010-001-MY3, 103-2628-B-010-040-MY3, 104-2811-B-010-020 and 104-2320-B-010-041-MY3), Yen Tjing Ling Medical Foundation (CI-104-10 and CI-104-13), and Ministry of Education, Aim for the Top University Plan, Taiwan.

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  1. Department of Physiology, School of Medicine, National Yang-Ming University, Taipei, 11211, Taiwan

    Kuan-I Lee, Hui-Ching Lin & Tzong-Shyuan Lee

  2. Institute of Anatomy and Cell Biology, National Yang-Ming University, Taipei, Taiwan

    Hsueh-Te Lee & Feng-Chuan Tsai

  3. Genome Research Center, National Yang-Ming University, Taipei, Taiwan

    Tzong-Shyuan Lee

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  1. Kuan-I Lee
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Lee, KI., Lin, HC., Lee, HT. et al. Loss of Transient Receptor Potential Ankyrin 1 Channel Deregulates Emotion, Learning and Memory, Cognition, and Social Behavior in Mice. Mol Neurobiol 54, 3606–3617 (2017). https://doi.org/10.1007/s12035-016-9908-0

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